Lipoxygenases (E.C. 1.13.11.12) are enzymes occurring in platelets, leukocytes, lymphocytes, etc., and converting polyunsaturated fatty acids (in particular arachidonic acid) to hydroperoxides. The positions 5, 8, 9, 11, 12 and 15 are known to be available for the introduction of a hydroperoxy group into arachidonic acid by lipoxygenases. Thus, for instance, the lipoxygenase occurring in relatively large amounts in platelets is 12-lipoxygenase which hydroperoxidizes arachidonic acid at the position 12, while 5-lipoxygenase and 15-lipoxygenase are reportedly present in leukocytes. Hydroperoxyeicosatetraenoic acids produced from arachidonic acid by the action of lipoxygenases are unstable and are converted to the corresponding hydroxyeicosatetraenoic acids.
Recent studies have revealed that these fatty acids which lipoxygenases produce and in vivo metabolites thereof have various physiological activities. For example, it has been demonstrated that the slow reacting substance of anaphylaxis which is produced in the lung of anaphylactic guinea pigs and in the human lung on the occasion of asthmatic attack and which causes contraction of the bronchial smooth muscle essentially consists of leukotrienes C, D, E and F which are 5-lipoxygenase-mediated metabolites of arachidonic acid [Samuelson et al., Proc. Natl. Acad. Sci., U.S.A., 77, 2014 (1980)]. Further, 12-hydroperoxyeicosatetraenoic acid (12-HPETE) and 12-hydroxyeicosatetraenoic acid (12-HETE), which are 12-lipoxygenase-mediated metabolites, exhibit a variety of physiological activities, such as leukocyte migrating activity, neutrophil attracting activity, platelet thromboxane synthetase inhibiting activity, prostacycline synthetase inhibiting activity and smooth muscle cell migrating activity [cf. Seiitsu Murota (ed.), Prostaglandin to Byotai (Prostaglandins and Pathology), published by Tokyo Kagaku Dojin, 1984].
As mentioned above, it has been reported that the lipoxygenase-mediated metabolites cause stimulation of peripheral blood vessel permeability, leukocytotaxis, and contraction of various types of smooth muscle such as the smooth muscle of the respiratory system (trachea, bronchi, lung tissues), vascular system or digestive system. Thus, the lipoxygenase-mediated metabolites have been considered to cause bronchial asthma, allergic diseases (atopic dermatitis, inflammation of organs, etc.) and diseases of the cirulatory system (edema, ischemic heart diseases, hypertension, ischemic encephalopathy, arteriosclerosis, etc.); they are also chemical mediators inducing inflammatory diseases. Therefore, artificial suppression of the lipoxygenase activity by means of some specific inhibitors might possibly lead to successful prevention and/or treatment of the above-mentioned diseases.
Among compounds known to have lipoxygenase inhibiting activity, there are AA-861, BW-755C, etc. Pharmacologically, BW-755C has anti-inflammatory and other activities and AA-861 has bronchial contraction suppressing, anti-inflammatory, anti-myocardiac infarction and other activities [T. Yoshimoto et al., Biochim. Biophys. Acta, 713, 470 (1982); G.A. Higgs et al., Biochem. Pharmacol., 28, 1959 (1975); Y. Maki et al., Prostaglandins, 26 (6), 955 (1983); K. Sasaki et al., Adv. Prostaglandin, Thromboxane & Leukotriene Res., 17, 381 (1987)].
U.S. Pat. Nos. 4,623,661, 4,604,407, 4,608,390, 4,605,669, 4,738,986, 4,771,038, 4,728,670 EP-A-254 852 and GB-A-2 189 486 disclose certain hydroxamic acid derivatives having lipoxygenase inhibiting activity.
H. Bickel et al., Helv. Chim. Acta., 43, 2129 (1960) and S. Adapa et al., ibid., 65, 1818 (1982) describe desferri-ferrioxamines having the following formulae: ##STR2##
The desferri-ferrioxamines are compounds derivable from the corresponding ferrioxamines isolated from actinomycete fermentation products as growth factors for microorganisms, by removal of the iron atom therefrom. The reports so far published on the ferrioxamines and desferri-ferrioxamines do not make any mention of the lipoxygenase inhibiting activity.
Hithertofore, several types of lipoxygenase inhibiting compounds have been reported. In most cases, however, the inhibitory activity is relatively low or is non-specific, namely poorly distinguishable from the inhibitory activity against other enzymes [cf. T. Schewe et al., Adv. Enzymol., 58, 191 (1986)]. Accordingly, the development of better lipoxygenase inhibitors which have high inhibitory activity and can remain effective in vivo has been awaited.